Nefazodone

At Nefazodone is a pharmacological agent that is used in the treatment of depression. The substance belongs to the group of so-called dual serotonergic antidepressants. Nefazodone is a phenylpiperazine derivative and, in terms of its structure and, in some cases, its effects, is similar to the antidepressant trazodone, which was discovered earlier.

What is nefazodone?

Nefazodone is an active ingredient that belongs to the group of serotonin-norepinephrine reuptake inhibitors. This makes the active ingredient one of the antidepressants. Due to serious liver-toxic side effects, nefazodone is no longer marketed today. Before that, the drug was available from 1997 in Germany under the trade name Nefadar®. Several cases of severe liver failure resulted in the drug nefazodone being withdrawn from the market in Germany in 2003.

Basically, the substance nefazodone is in pharmacological use as nefazodone hydrochloride. It is a crystalline powder with a white color and poor solubility in water. Nefazodone is a derivative of triazole and phenylpiperazine. It also has structural similarities to the substance trazodone.

Pharmacological effect

Nefazodone is an antidepressant whose exact mechanism of action is not yet fully understood. The interaction with so-called serotoninergic mechanisms is relevant in any case. Because nefazodone has a dual effect on serotoninergic neurotransmission. On the one hand, the substance reduces special postsynaptic receptors that are designed for serotonin. On the other hand, nefazodone partially stops the presynaptic absorption of the substance.

Certain active metabolites also affect the serotonin receptors. It is also relevant for the effect that nefazodone has no appreciable affinity for dopaminergic, histaminergic and cholinergic receptors.

In addition to serotonin, nefazodone also inhibits the neuronal reuptake of the messenger substance norepinephrine. In addition, the drug nefazodone has hepatotoxic properties, which is why it has led to serious liver diseases in some cases.

The effect on the serotonin receptor is primarily antagonistic. Thus the concentration of the monoamine increases. The concentration of serotonin only increases again when the responsible serotonin transport substance is restricted. This is responsible for ensuring that the monoamine gets out of the synaptic gap again. Nefazodone develops its effect as an inhibitor for serotonin and its renewed absorption.

In addition, however, nefazodone has a weak inhibition of certain enzymes, which is why it has fewer undesirable side effects than similar drugs from the same category such as paroxetine and fluoxetine.

The drug nefazodone is completely absorbed by the gastrointestinal route and in a relatively short time. The maximum concentrations in the plasma of the blood result approximately two hours after ingestion. Since the presystemic metabolism is very strong, the bioavailability of the pharmaceutical substance is only around 20 percent. It is therefore advisable to take the drug together with a meal, since under these circumstances the so-called systemic availability can increase by up to 18 percent.

The metabolism of the drug nefazodone takes place in the liver and takes place with the help of the cytochrome CYP3A4. At the same time, it is a substance that severely affects the cytochrome. The three active metabolites are the substances meta-chlorophenylpiperazine, hydroxynefazodone and triazoldione. However, hydroxynefazodone is mainly of particular clinical importance. This substance is able to reach high concentrations and has similarities to nefazodone.

Medical application & use

The drug nefazodone is used for a number of mental illnesses. First and foremost, it is a drug that is used in the therapy of depression. In addition, nefazodone is also prescribed for obsessive-compulsive disorder, borderline syndrome or panic attacks, for example.

The drug is usually taken orally. The bioavailability of the substance is around 20 percent. The active ingredient binds completely to plasma proteins in the blood. Nefazodone is mainly excreted in the urine and minimally in the stool.

If the dose of hydroxynefazodone is only slightly increased, disproportionately higher concentrations in the plasma are the result. In principle, the plasma half-life of the two substances is around two hours and, after taking them again, around three and a half hours. In people who are over 65 years of age and people who suffer from impaired liver function, the plasma levels are significantly higher than in patients who are young and without health problems.

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Risks & side effects

A number of various undesirable side effects are possible when taking nefazodone. These depend in part on the dose. This sometimes leads to drowsiness, dizziness, nausea and dry mouth. Visual disturbances such as blurred vision are also possible. In some cases, the symptoms gradually subside slightly as the duration of treatment increases.

Less common side effects include withdrawal symptoms, hair loss, and hypoglycemia. Sexual disorders are also possible. In individual cases, severe liver dysfunction has been observed, which can occur weeks or months after therapy. If nefazodone is taken together with MAO inhibitors, the affected patients sometimes suffer from suicidal thoughts.